MutT is an enzyme first identified in Escherichia coli that reportedly dephosphorylates 8-oxo-dGTP, a metabolite known to promote high levels of AT to CG transversion mutations (Bhatnagar et al., J Biol Chem., 1991, 266:9050-4). A mutT strain of Escherichia coli that lacks this catalytic activity has an increased spontaneous mutation rate of up to 104-fold (Bessman et al., J Biol Chem., 1996, 271:25059-62). Mammalian counterparts of this important antimutator dGTPase have been identified (Mo et al., Proc Nail Acad Sci USA., 1992, 89:11021-51992).
More recently, additional polypeptides sharing a small, localized region of homology with MutT have been identified. This region of homology is referred to herein as the MutT domain, with a sequence of GXXXXXEXXXXXXXREUXEEXXU (SEQ ID NO. 4), wherein X represents any amino acid and U represents an amino acid with an aliphatic side chain. Members of this newly identified MutT family of polypeptides are believed to act as homeostatic checkpoints at some important stages in the nucleoside phosphate metabolic pathways, guarding against the potentially dangerous consequences of elevated levels of a small number of these intermediates (Bessman et al., supra; O'Handley et al., J Biol Chem., 1998, 273:3192-7).
Certain other MutT family members have been proposed to protect the cell from the deleterious consequences of inappropriate activation of some signal transduction processes, by catabolizing additional nucleoside phosphates that may have cell signaling roles (Bessman et al., supra). For example, hydrolysis of dATP by the MutT module (O'Handley et al., J Biol Chem., 1996, 271:24649-54) may, in mammals, guard against this molecule providing an untimely initiation of apoptosis (Liu et al., Cell, 1996, 86:147-57). Diadenosine polyphosphates, which mediate cellular stress responses (Kisselev et al., FEBS Lett, 1998, 427:157-63), are also metabolized by this protein family (Thorne et al., Biochem J, 1995, 311 (Pt 3):717-21). To date, ˜15 MutT family members have been characterized, all of which appear dedicated to the metabolism of nucleoside phosphates (Bessman et al., supra).
Despite the foregoing similarities, MutT family members appear to vary in their substrate specificity. MutT substrates reportedly include nucleoside triphosphates, coenzymes, nucleotide sugars, and dinucleoside polyphosphates. It has therefore been suggested that these enzymes are involved in diverse metabolic pathways, and function by cleansing the cell of potentially deleterious endogenous metabolites, and/or modulate the accumulation of intermediates in biochemical pathways.